Radiotherapy is the most important non-surgical treatment for cancer. Even so, large numbers of patients still fail at the local treatment site. New treatment strategies aimed at improving tumor response are therefore of high interest and the tumor vasculature, which is critical for the growth and survival of the neoplastic cell population, offers an attractive target. The goal of this grant proposal is to investigate approaches for optimally combining antiangiogenic strategies with localized radiation therapy in order to improve overall tumor response. Investigations are focused on interfering with two activators of angiogenesis (vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF)) and amplification of an endogenous suppressor (endostatin). The approach will be the delivery and transfer of cDNA coding for antisense VEGF/bFGF or endostatin using adeno-associated virus (AAV) or cationic liposomes. Experiments are designed to first characterize and optimize the proposed antiangiogenic approaches in tumor cells, fibroblasts and endothelial cells in vitro. These studies will include the examination of the effect of angiosuppression strategies on the paracrine communication between the various cell types and the determination of whether direct interactions occur between such strategies and radiation treatment. The in vivo efficacy of antiangiogenic treatments used in conjunction with radiation therapy will then be evaluated in xenograft models of AIDS associated Kaposi's Sarcoma and clear cell renal cell carcinoma. These models were chosen because we believe that these neoplasms' typical manifestation of extensive vascularization, coupled with their lack of satisfactory responses to traditional therapeutic interventions, make them excellent candidates for new therapeutic strategies such as antiangiogenic approaches. Both tumor response and critical normal tissue toxicities will be assessed to determine whether a therapeutic benefit can be achieved when angiosuppressive treatments and radiation are combined. We believe that these studies will provide essential insights into the therapeutic utility of employing antiangiogenic treatment strategies as adjuvants to radiotherapy.